Tricyclic amines and processes for the preparation thereof

ABSTRACT

1-Chloro- or 1-fluoro- derivatives of 5H-dibenzo(a, d)cycloheptenes and 1-chloro- or 1-fluoro- derivatives of 10,11dihydr-5H-dibenzo(a,d)cycloheptenes having, at position 5, a basic exocyclic side chain of the formula   WHEREIN R1 is hydrogen or methyl, AND INTERMEDIATES THEREFOR ARE PREPARED BY ALTERNATE PROCEDURES. The described end-products are useful, for example, as psychopharmacological antidepressants.

United States Patent 1 Kyburz et al.

[451 May 20, 1975 TRICYCLIC AMINES AND PROCESSES FOR THE PREPARATIONTHEREOF [75] Inventors: Emilio Kyburz, Reinach; Hans.

Spiegelberg, Basel, both of" Switzerland [73] Assignee: Hoffmann-LaRocheInc., Nutley,

[22] Filed: Mar. 8, 1974 [2]] App]. No.: 449,405

Related US. Application Data [60] Division of Ser. No. 107,499, Jan. 18,l97l, abandoned, which is a continuation-in-part of Ser. No. 679,644,Nov. 1, 1967, abandoned.

[52] US. Cl 260/501.1; 260/465 E; 260/505; I

260/561 R; 260/561 B; 260/566 F; 260/5766 M; 260/570.6; 260/570.8 TC;260/590;

[51] Int. Cl. C07c 119/00 [58] Field of Search 260/566 F, 566 R, 50l.1

[56] References Cited UNITED STATES PATENTS Primary ExaminerGerald A.Schwartz Attorney, Agent, or FirmSamuel L. Welt; Bernard S. Leon;William G. Isgro Rey-Bellet et a1. 260/566 F wherein R is hydrogen ormethyl, and intermediates therefor are prepared by alternate procedures.The described end-products are useful, for example, aspsychopharmacological antidepressants.

1 Claim, No Drawings TRICYCLIC AMINES AND PROCESSES FOR THE PREPARATIONTHEREOF This is a division of application Ser. No. 107,499 filed Jan.18, 1971 which in turn is a continuation-in-part application of Ser. No.679,644, filed Nov. 1, 1967, both of which are now abandoned.

BACKGROUND OF THE INVENTION H-Dibenzo[a,d]cycloheptenes and10,1l-dihydro- SI-I-dibenzo [a,d]cycloheptenes having a basic side chainin the 5-position, for example, 10,1 l-dihydro-S-3-dimethylaminopropylidene )-5H-dibenzo[ a,d]cycloheptene(amitriptyline) and 10,1 l-dihydro-5-(3-methylaminopropylidene)-5I-I-dibenzo[a,d]cycloheptene (nortriptyline),are known for their psychopharmacological antidepressant properties.

The compounds of this invention of hereinafter described formulas Ia andlb, which differ from the prior art compounds by the presence of achlorine or fluorine at position-l, unexpectedly exhibit substantiallyincreased antidepressant activity and significantly decreased toxicity.Also, they show a substantial absence of anticholinergic activity.Anticholinergic activity is not desirable in psychopharmacologicalantidepressant compounds, and its absence is particularly advantageous.Additionally, the compounds of formulas la and lb are characterized bytheir action on the nervous systems, for example, they possess narcosispotentiating, adrenolytic, sedative, antihistaminic and local anestheticactivities.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to novelderivatives of 5H- dibenzo [a,d]cycloheptenes useful aspsychopharmacological antidepressant agents and to novel intermediatesuseful in the preparation thereof. In particular, the

' invention relates to psychopharmacological antidepressant tricyclicamines of the formulas CH -CH -CH -N and R Ib

CH-CH CH -N\ wherein R is chlorine or fluorine, R is hydrogen or methyl,R and R are hydrogen, chlorine or fluorine, and X is ethylene, vinyleneor halo-substituted vinylene, and the pharmaceutically acceptable acidaddition salts thereof. The compounds of formulas Ia and lb and theirpharmaceutically acceptable salts are useful, for example, aspyschopharmacological antidepressants.

DETAILED DESCRIPTION OF THE INVENTION This invention relates totricyclic amines of the formulas CHCH -CH N wherein R is selected fromthe group consisting of chlorine and fluorine, R is selected from thegroup consisting of hydrogen and methyl, R and R are selected from thegroup consisting of hydrogen,

chlorine and fluorine and X is selected from the group consisting ofethylene, vinylene and halosubstituted vinylene, and pharmaceuticallyacceptable acid addition salts thereof.

As used herein,- the terms halo and halogen denote chlorine, bromine,fluorine and iodine, preferably chlorine and bromine. As used herein,the term lower alkyl denotes a straight chain or branched chain alkylgroup containing 1-7 carbon atoms, e.g., methyl, ethyl, propyl,isopropyl, butyl, pentyl, hexyl and the like.

Unsymmetrically substituted compounds of formula Ib, which have anexocyclic double bond in the 5- position, form geometricisomers whichhereinafter will be referred to as the aor the B-isomer. This inventionincludes all the geometric isomers of the compounds of formula Ibwhether they be obtained as mixtures or as an individual isomer, Theisomers of the compounds of formula Ib exhibit psychopharmacologicalantidepressant activity as well as the other activities mentionedhereinbefore, and are particularly useful as psychopharmacologicalantidepressants.

Unsymmetrically substituted compounds of formula la form opticalisomers. These isomers as well are included in the invention. They showthe same useful activities as indicated hereinbefore.

A preferred subgenus of the compounds of formula la is represented bythe formula R1 cH -cH2 Hzwherein R is hydrogen or methyl, R and R arehydrogen, chlorine or fluorine, and X is ethylene, vinylene orhalo-substituted vinylene, and pharmaceutically acceptable acid additionsalts thereof.

A more preferred subgenus comprises a compound of formula lc wherein Rand R are hydrogen.

A preferred subgenus of the compounds of formula lb is represented bythe formula CH-CH --CH -N wherein R is hydrogen or methyl, R and R arehydrogen, chlorine or fluorine, and X is ethylene, vinylene, orhalo-substituted vinylene, and pharmaceutically acceptable acid additionsalts thereof.

A more preferred subgenus comprises a compound of formula ld wherein Rand R are hydrogen.

Compounds of this invention corresponding to formulas la and lb areexemplified by the following:

l-chlorol 0,1 l-dihydro-5-( 3-methylaminopropyl5H-dibenzo-[a,d]cycloheptene;

l-chloro-5-(3-dimethylaminopropylidene)-5H- dibenzo[a,d]cycloheptene;

the B-isomer of l-chloro-5-( 3- dimethylaminopropylidene )-5H-dibenzoa,d]cycloheptene;

1-chloro-5-( 3-methylaminopropylidene )-5l-l-diben zo[a,d]cycloheptene;

l-chloro-lO (or 1 l)-bromo-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene;

1,10 (or ll)-dichloro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene;

1,3-dichloro- 10,1 l-dihydro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene;

the ,B-isomer of 1,3-dichloro-10,l l-dihydro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene;

l,3-dichloro-10,l l-dihydro-5-(3-dimethylaminopropyl)-5l-l-dibenzo[a,d]cycl0heptene; and

l,9-dichlor0-10,1 l-dihydro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene.

The tricyclic amines of the invention can be prepared utilizing severalalternate processes, for example:

1. A compound of the formula X L l a I R2 Y1 CH-CH2-CH2-N Y2 CH3 whereinR, R R R and X are as previously described and one of Y or Y is hydrogenand the other is hydroxy, can be reduced or dehydrated to form thecorresponding compound of formulas Ia or lb; 2. A compound of theformula VI III 1 wherein R. R R and X are as previously described and Wis halogen, can be reacted with a dimethylaminopropyl magnesium halideto form the corresponding compound of formula la;

3. A compound of the formulae wherein R, R R and X are as describedabove, Z is halogen or a substituted sulfonyloxy residue, and A is theanion of an acid, can be treated with methylamine or dimethylamine toform the corresponding compound of formulas In or lb;

4. A primary amine of the formula OI R IV'o R R 3 l l 2 Ii -Z CH CH2 40H-CH -CH -I\IH R wherein R, R R and X are as previously described,

can be methylated to form the corresponding com- Va pound of formulas laor lb; N 5. A compound of the formula R3 2 R X VIIIa VIIIb cn-cn -cn -mCH3 A 7 wherein R, R R and X are as previously described, can bedebenzylated to form the corresponding compound of formulas Ia or lb; 6.A compound of the formula wherein R, R R and X are as previouslydescribed,

and T is an alkali-metal atom, such as sodium, po-

tassium and the like, can be reacted with a compound of the formula c f-XI L-CH -CH -QH -N wherein L is a halogen or a substituted sulfonyloxyresidue, to form the corresponding compound of formula Ia; or

8. A compound of the formula t XII sa on -ea n wherein R, R R and X areas previously described,

and D is acyl or an esterified carboxyl,

can be hydrolytically cleaved, whereupon, if desired, in optionalsequence, if a monomethylamino compound'is obtained, it can bemethylated; if a dimethylamino compound is obtained, it can be convertedby demethylation into a monomethylamino compound; if a product with anunsubstituted ethylene or vinylene group X is obtained, this group canbe converted into a halogenated vinylene group; if a 10,1l-dihydro-compound is obtained, it can be dehydrogenated. Furthermore,if desired, the geometric or optical isomers can be isolated from anisomeric mixture obtained, and a base obtained can be converted into asalt.

According to a preferred embodiment of a process of theinvention,a'carbinol of general formula II is reduced or dehydrated. Preferredstarting substances are compounds of formula II wherein Y is a hydroxyland Y; is hydrogen. The reduction of compounds of formula ll leads toexocyclically saturated compounds of formula la. The reduction may beconveniently carried out with a nascent hydrogen produced by reacting,for

example, zinc in glacial acetic. Another very suitable 3 reducingagentis hydroiodic acid. By treatmentof a compound of formula II withhydroiodic acid, espeperature in the range of room temperature and theboiling point of the reaction mixture.

The dehydration of compounds of formula II leads to compounds of formulalb, having an exocyclic double bond in the 5-position. This dehydrationis conveniently carried out using a mineral acid, such as, hydrochloricor hydrobromic acid, in which case'the dehydration can be carried out inan anhydrous or an aqueous medium. The dehydration is preferably carriedout in ethanolic hydrochloric acid at a temperature in the range of roomtemperature and the boiling point of the reaction mixture. However,dehydration can also be accomplished utilizing heat, for example, at50C. to reflux temperature, preferably at reflux temperature, with ahigh-boiling anhydrous solvent, such as, dimethyl sulfoxide. Other knowndehydrating agents can i also be employed, for example, acetyl chloride,acetic acid anhydride, trifluoroacetic acid anhydride, sulfuric acid,phosphorus oxychloride, p-toluenesulfonyl chloride, zinc chloride,potassium bisulfate, or the like. An inert organic solvent, such aschloroform, methylene chloride, or the like, can be employed at atemperature in the range of room temperature and the boiling point ofthe reaction mixture.

The carbinol of formula II can be prepared by known procedures, forexample, by reaction of the corresponding tricyclic S-ketone withsuitable Grignard compounds. The tricyclic ketones of the formula I XVwherein R, R R and X are as previously described, can be prepared bymethods known per se (see e.g. J.Med.Chem. 8(6) 1965). These methods arealso illustrated in Examples 9, l l, l2, l3 and I5 hereinafter. It is tobe noted that the introduction of a halogen atom into the 10 (or 1 1)-position of l-chloro (or fluoro)-5H-dibenzo[a,d]cyclohepten-5-one ispreferably effected by addition of the desired halo gen withsimultaneous irradiation. After addition of an alkali, the resultingl-chloro (or fluoro)-l0,l dihalo- 10,1 l-dihydro-5H-dibenzo[a,d]cyclohepten-5-one splits off one molecule of hydrogen halide, wherebythe l-chloro (or fluoro)-lO (or ll)-halo-5l-l-dibenzo[a,d]cyclohepten-5-one is obtained.

Carbinols of formula II wherein Y, is hydroxyl and Y is hydrogen areconveniently obtained as follows:

When a carbinol of formula II wherein R is methyl is to be prepared, thecorresponding tricyclic 5- ketone propyl magnesium chloride, and thereaction product is subsequently hydrolyzed. If R, is hydrogen, it ispreferred to use methyl-benzyl-aminopropyl magnesium chloride as thereagent for the reaction. After complete reaction and subsequenthydrolysis, the resulting product is reacted with ethyl chloroformate toform 5- hydroxy-S 3-( methyl-carbethoxy-amino )-propyl] compound whichis hydrolyzed, whereupon a spontaneous decarboxylation occurs with theconcurrent formation of the corresponding 5-hydroxy-5-(3-methylaminopropyl) compound. Carbinols of formula II, wherein Y, ishydrogen and Y is hydroxyl are obtained, for example, by reacting acorresponding tricyclic S-ketone with ethyl magnesium bromide andhydrolyzing the reaction product. The resulting S-hydroxy-S-ethylcompound is dehydrated with acetyl chloride and, subsequently, treatedwith formic acid and hydrogen peroxide. The 5hydroxy-5-( lhydroxyethyl)compound which forms is dehydrated with aqueous sulfuric acid to yieldthe corresponding S-acetyl compound. By treatment with formaldehyde .andmethylor dimethylamine hydrochloride, there is obtained a S-(methylordimethylaminopropionyl) compound which, after reduction with sodiumborohydride, yields the corresponding carbinol.

According to another embodiment of a process of the invention, a halideof formula lllis reacted with a dimethylaminopropyl magnesium halide toform the corresponding exocyclically saturated compound of formula la.This process is particularly suitable for the preparation of thoseexocyclically saturated compounds of formula la which simultaneouslycarry a double bond in the 10,1 l-position. Preferably, a compound offormula III wherein W is chlorine, in a solid, finely powdered form orin an organic solvent, such as, for example, absolute ether, benzene,tetrahydrofuran, or the like, is introduced into a suspension ofdimethylaminopropyl magnesium chloride in one of the solvents mentionedhereinbefore. The reaction is conveniently carried out at a temperaturein the range of room temperature and the boilingpoint of the reactionmixture. After complete reaction, the reactionproduct is subjected tohydrolysis, preferably under practically neutral conditions, forexample, by treatment with aqueous ammonium chloride solution.

The starting halide of formula Ill can be prepared according to knownmethods, for example, by the reduction of the corresponding tricyclic5-ketone and subsequent halogenation of the resulting S-hydroxycompound.

A further embodiment of a process of the invention comprises treating acompound of general formulas lVa, IVb, Va, Vb or Vl with methylamine ordimethylamine. In the above formulas Na and lVb, Z preferably is achlorine or bromine atom. The substituted sulfonyloxy residues, as ameaning for Z, are preferably lower alk'yl-sulfonyloxy residues, such asmesyloxy; phenylsulfonyloxy residues; lower alkylphenylsulfonyloxyresidues, such as tosyloxy; or phenyl-(lower alkyl)-sulfonyloxyresidues, such as phenylmesyloxy. The anion A is preferably derived froman inorganic acid, such as, hydrochloric acid, hydrobromic acid,bydroiodic acid, sulfuric acid or the like.

The reaction of methylor dimethylamine with a compound of formulas Waror lVb, especially those wherein Z is halogen, represents a preferredprocess of the invention. 1

The reaction of compounds of formulas lVa, IVb, VA, Vb or Vl withmethylor dimethylamine is conveniently carried out in a closed vessel atelevated temperature, preferably in the raiige of about l75C.

The reaction can be effected in an inert organic solvent, such asmethanol, ethanol, benzene, toluene or the like. Preferably, thereaction is conducted in the presence of an excess of methyl ordimethylamine. In the case of reaction of compounds of formulas [Va andlVb, the excess amine serves as an acid-binding agent. Otheracid-binding agents, such as, anhydrous potassium carbonate, can also beemployed. The compounds of formula VI are preferably reacted in thepresence of a metal, such as, for example, sodium or lithium, a metalamide, such as, for example, sodium or potassium amide, or ametal-organic compound, such as, for example, phenyl-lithium or aGrignard compound. Particularly advantageous is the use of a Grignardcompound.

The starting compounds of formulas lVa and Nb can be prepared, forexample, by reaction of the corresponding tricyclic S-ketone withmethoxypropyl magnesium halide, subsequent hydrolysis, reduction ordehydration of the resulting carbinol, and treatment of the dehydratedproduct with a halogenating agent. The quaternary salts of formulas Vaand Vb, which can also I be employed as the starting material, can beobtained by quaternization of the corresponding amino, monomethylaminoor dimethylamino compound with a methylating agent, such as methylchloride, methyl bromide, methyl iodide, dimethyl sulfate, or the like.The starting compound of formula V1 is obtainable, for example, from thecorresponding tricyclic -ketone by reaction with an allyl Grignardcompound,

According to another process of the invention, a primary amine offormulas Vlla or Vllb is methylated. The methylation can be carried' outby treatment with a known methylating agent, such as, for example,methyl iodide, methyl tosylate, dimethyl sulfate, or the like,preferably at a temperature in the range of l575C. According to anotherprocedure, a mixture of formaldehyde and formic acid, preferably inexcess, is reacted with a primary amine of formulas VIIa or Vllb at anelevated temperature in the range of about 50C. and the boiling point ofthe reactionmixture.

A preferred process for the preparation of secondary amines of formulasIa or lb comprises reacting the corresponding primary amine of formulaVIIa or Vllb with a haloformic acid ester, such as, for example,chloroor bromoformic acid ethyl ester, to form a carbamate, and,subsequently, reducing the carbamate with a metal hydride, such as,lithium aluminum hydride, diisobutyl aluminum hydride, or the like. Bothreaction steps are preferably carried out in an inert solvent, forexample, ether, tetrahydrofuran, or the like, at a temperature in therange of about room temperature and the reflux temperature of thereaction mixture, preferably at reflux temperature.

According to another process for the preparation of secondary amines offormulas Ia or lb, a primary amine of formulas VIla or Vllb is reactedwith chloral, preferably in an inert solvent, such as chloroform,benzene, or the like, at an elevated temperature in'the range of about50C. and the boiling point of the reaction mixture. The resultingformylamino compound is reduced to the secondary amine corresponding toformulas la or lb with a metal hydride, such as, lithium aluminumhydride, in anhydrous ether.

Still another process for the preparation of secondary amines offormulas la or lb comprises the reaction of a primary amine of formulasVlla or Vllb with-formaldehyde, preferably in an inert solvent such asbenzene,

toluene, and the like, at a temperature in the range of about roomtemperature and the boiling point of the reaction mixture. TheresultingSchiffs base is subse quently converted into the corresponding secondaryamine of formulas la or lb by reduction. This reduction is convenientlyeffected witha metal hydride, such as, sodium borohydride or lithiumaluminium hydride, in anhydrous ether or dioxane.

The starting compounds of formulas VIIa and Vllb can be obtained inseveral ways. The aminopropylidene compounds of formula Vllb areobtained, for example, by exchange of the keto group of thecorresponding 5- ketone with an ethylidene group, for example, by meansof Grignard, and subsequent halogenation, treatment with a cyanide, andhydrolysis. The aminopropyl compounds of formula VIIa are convenientlyprepared by reaction of the corresponding 5- methoxypropyl orS-methoxypropyl-S-hydroxy compound with hydrogen iodide, treatment ofthe resulting iodopropyl compound first with potassium phthalimide and,subsequently, with hydrazine.

According to a further process of the invention, compounds of formulasVllla or Vlllb are debenzylated. In the debenzylation, the benzyl groupbound to the nitrogen atom is exchanged for a hydrogen atom, to yieldthe corresponding secondary amine offormulas la ;or lb. This reaction isconveniently carried out by reduc- 12 tion with an alkali metal, 'suchas, for example, sodium or lithium, in liquid ammonia. In thedebenzylation procedure, the double bonds which are present aresubstantially retained.

The starting compounds of formulas Vllla and Vlllb are convenientlyobtained by the reaction of the corresponding compound of formulas IVa,IVb, Va, Vb or VI with methylbenzylamine.

A still further process of the invention comprises the treatment of acompound of formula IX with aqueous acid at elevated temperature,resulting in the dehydration of the carbinol of formula IX. Thesubstituent Q is simultaneously removed and there results thecorresponding secondary amine of formulas la or Ib. in formula IX, Qpreferably is the residue of an aromatic aldehyde, such' as, forexample, benzylidene or the like. The residue B preferably is the anionof a strong inorganic or organic acid, such as, for example,hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonicacid, or the like, particularly preferred is the anion oftoluenesulfonic acid. According to a preferred embodiment, a compound offormula IX, wherein P is hydroxyl and P is hydrogen, is reacted withaqueous sulfuric acid at a temperature in the range of about -l50C.

The starting compound of formula IX is obtained, for example, byreacting the corresponding S-hydroxy-S- (3-aminopropyl) compound(prepared by reacting the corresponding 5-ketone with an alkalimetal andtreatment of the resulting alkali-metal compound with an aminopropylhalide), a corresponding 5-(3-amino-1- hydroxypropyl) compound (preparedby reacting the corresponding 5-acetyl compound with formaldehyde andammonium chloride, followed by reduction with sodium borohydride) or acompound of formulas VIIa or VIIb with an aldehyde, such as, forexample, benzaldehyde and quatemizing the resulting Schiffs base with aknown methylating agent, such as, methyl chloride, dimethyl sulfate,methyl mesylate, methyl benzenesulfonate or the like; particularlypreferred is methyl tosylate, at an elevated temperature. The compoundof formula IX which is obtained can be utilized without furtherpurification. Often, it is advantageous not to isolate it, butimmediately to allow the reaction mixture to react with the aqueous acidat an elevated temperature as discussed above.

A further process of the invention comprises the reaction of a compoundof formula X with a comound of formula XI to form the exocyclicallysaturated compounds of formula Ia. In formula X, the symbol T preferablyis sodium, potassium or lithium. L in formula XI is preferably chlorine.In its significance as a substituted sulfonyloxy residue, L preferablyis a lower (cyclo-) alkylsulfonyloxy residue, such as, mesyloxy orcyclopropylsulfonyloxy; the phenylsulfonyloxy residue; a loweralkylphenylsulfonyloxy residue, such as, tosyloxy; or a phenyl-(loweralkyl)-sulfonyloxy residue, such as phenylesyloxy. The reaction isconveniently carried out in an inert solvent such as benzene, toluene,hexane, heptane, ether or the like, at a temperature in the range ofabout the room temperature and the boiling point of the reactionmixture.

The starting compound of formula X can be obtained, for example, by thetreatment of the corresponding S-ketone or 5-hydroxy compound withaluminum isopropoxide, and subsequent reaction with an al-, kali-metalamide or hydride.

According to a still further process of theinvention, compounds ofgeneral formula XII are hydrolytically cleaved to yieldthe correspondingsecondary amines of formula la. The group D can be, for example, acyl,such as, a lower alkanoyl group, for example, formyl or acetyl; aphenyl-(lower alkanoyl), for example, benzoyl; a lower alkylsulfonyl,for example, mesyl; phenylsulfonyl; lower alkylphenylsulfonyl, forexample, tosyl; or phenyl-(lower alkyl)-sulfonyl, for example,phenylmesyl. The group D, in its significance as an esterified carboxygroup, preferably is lower carbalkoxy, for example, carbomethoxy,carbethoxy or carboisopropoxy; carbophenoxy; or lower carbophenylalkoxy,for example, carbobenzoxy. When D is a non-sulfur-containing group, thecleavage proceeds under the conditions which are employed for acidic oralkaline hydrolysis, for example, with heating, for example, at atemperature in the range of about 50C. and the boiling point of thereaction mixture, in the presence of an ethanolic solution ofhydrochloric acid, acetic acid, sodium hydroxide or potassium hydroxide.Alkaline hydrolysis is preferred. When D is a sulfur-containing group,it is preferred to conduct the cleavage by treatment with, for example,hydrobromic acid in acetic acid in the presence of phenol, analkali-metal, such as sodium, and a high-boiling alcohol, such as,butanol or hydroiodic acid and phosphonium iodide. Such reactions areconveniently effected with heating, for example, at a temperature in therange of about 50C. and boiling point of the reaction mixture. Anothermethod for the cleavage of sulfur-containing group comprises treatmentwith liquid ammonia and an alkali-metal, such as, sodium.

The starting compound of formula X-ll can be obtained, for example, byheating a compound of formula X in ether with a methyl-D-aminopropylhalide, wherein D is as described above,

The compounds of formulas la and lb, prepared as described above, can,if desired, be subjected to additional transformations.

A methylamino compound of formulas la or lb can be transformed into adimethylamino compound according to known methods, for example, bytreatment with a methylating agent, such as methyl iodide, methylmesylate, methyl tosylate, dimethylsulfate or the like, preferably at atemperature in the range of about 1575C. According to another procedure,a mixture of formaldehyde and formic acid, preferably in excess, at anelevated temperature, for example, in the range of about 50C. and theboiling point of the reaction mixture, is reacted with the methylaminocompound of formulas la or lb.

Dimethylamino compounds of formulas Ia and lb can be transformed intothe corresponding monomethylamino compounds. An especially suitableprocess for this transformation comprises reacting the dimethylaminocompound of formulas la or lb with a cyanogen halide, preferably withcyanogen bromide. The reaction is conveniently carried out in an inertsolvent, such as, for example, benzene, ether, tetrahydrofuran,methylene chloride or the like,'at atemperature between room temperatureand the boiling point of the mixture. The resulting N-cyanoN-methylaminocompound is subsequently. hydrolyzed in a known manner in alkaline oracidic medium, whereby the monomethylamino compound of formulas la or lbis formed as a base or acid addition salt, depending on the hydrolysismedium employed.

According to another process for the demethylation of dimethylaminocompounds of formulas la or lb, said compounds are treated with ahaloformic acid ester and the resulting carbamate is hydrolyzed. Thealcoholic portion of the haloformic acid ester to be employed ispreferably derived from an alcohol, such a lower alkanol, for example,methanol, ethanol, or isopropanol; phenol; or a lower phenyl-alkanol,for example, benzyl alcohol. The halo portion preferably is chlorine.The reaction with the haloformic acid ester is conveniently effected ina high-boiling inert solvent, such as, xylene or toluene, at atemperature in the range of about 50C. and the reflux temperature of thereaction mixture, preferably at reflux temperature. The subsequenthydrolysis can be carried out under alkaline or acidic conditions, forexample, with potassium hydroxide in butanol or hydrogen bromide inglacial acetic, at a temperature in the range of about 50$C. and theboiling point of the reaction mixture.

Unsubstituted groups X, i.e. the ethylene group, X and the vinylenegroup X, can be converted into a halogen substituted vinylene group. Bytreatment with e.g. gaseous chlorine, preferably in an inert solventsuch as carbon tetrachloride and with the application of light, twochlorine atoms are added to the unsubstituted vinylene group X. Thetemperature is not critical but is preferably kept between roomtemperature and the boiling point of the reaction mixture. The ethylenegroup X can be treated with an excess ofa halogenating I 7 agent such asN-bromosuccinimide, N- chlorosuccinimide, bromine, chlorine or'sulphuryl chloride, whereby two hydrogen atoms in 10,1 1- position arereplaced by two halogen atoms. This reaction is preferably effected inan inert solvent such as carbon tetrachloride, benzene, heptane,chloroform or tetrahydrofuran and at elevated temperature, e.g. at 50Cto the boiling point of the reaction mixture. It is very advantageous toadd a small amount of a reaction initiator such as azo-bisbutyronitrileor dibenzoyl peroxide, as well as a hydrogen halide acceptor, e.g.pyridine, triethylamine, collidine, allyl chloride or an epox ide. Bytreatment of a so-obtained 10,1l-dihalogen- 10,1 l-dihydro compound withan inorganic or organic base, for instance caustic soda, potassiumcarbonate or triethylamine, one molecule of hydrogen halide is split offyielding compounds of the formulas la or lb with a halogen substitutedvinylene group in 10,1 l-position. The temperature for this purpose isnot critical but is preferably maintained between room temperature andthe boiling point of the reaction mixture.

10,1l-Dihydro compounds of the formulas la or lb can be dehydrogenatedin the 10,1 l-position. This is conveniently effected by heating e.g. atl50250C with a catalyst such as palladium carbon, Raney-nickel orplatinumdioxide, conveniently in an inert solvent such as, e.g.tetrahydronaphthalene or diethyleneglycol monomethyl ether.

According to another mode of dehydrogenation of 10,1 l-dihydro compoundsof the formulas la or lb there is proceeded as follows:

If a monomethylamino group is present, this is protected by theintroduction of a protecting group. Now one or two halogen atoms areadded in 10- and/or 1 1- position by means of halogenation. Thesehalogen atoms can be split off with the formation of a 10,11-

position.

double bond as discussed below. After splitting off any protecting grouppresent there is obtained an amine of the formulas la or lb which isunsaturated in 10,11-

Representative examples of suitable protecting groups are: the cyanidegroup or an esterified carboxy group, such as, carbomethoxy, carbethoxy,carboisopropoxy, carbophenoxy and carbobenzoxy. The cyanide group isconveniently introduced through reaction with a cyanogen halide,preferably with cyanogen bromide, for example, in an inert solvent, suchas benzene, ether, tetrahydrofuran or methylene chloride, at atemperature in the range of about room temperature and the boiling pointof the reaction mixture. The introduction of the esterified carboxygroup is effected, for example, through reaction with the correspondinghaloformic acid ester, such as, thelchloroformic acid ester. Thisreaction is preferably effected in an inert solvent, such as, forexample, chloroform, xylene, toluene or the like, at a temperature inthe range of about room temperature and the boiling point of thereaction mixture. When a monomethylamino compound of formulas la or lbis employed for the introduction of the cyanide group or of anesterified carboxy group, it is recommended to add an acid-bindingagent, such as triethylamine, pyridine or the like. The reaction thenprotion of amonomethylamino compound of formulas Ia or lb .with acetylchloride or acetic anhydride, conveniently in the presence of anacid-binding agent, such as, triethylamine, pyridine or the like. Thereaction can be effected at a temperature in the range of about roomtemperature and thereflux temperature of the reaction mixture; roomtemperature is often sufficient.

The l0,l l-dihydro compound which may be protected at the nitrogen atomis subsequently treated with a halogenating agent, such as,N-bromosuccinimide, N-chlorosuccinimide, bromine, chlorine sulfurylchloride or the like, whereby one or two hydrogen atoms are replaced byone or two halogen atoms in the 10- and/or 1 l-position, depending onthe amount used of halogenatin agent. The reaction is preferablyeffected in an inert solvent, such as, carbon tetrachloride, benzene,heptane, chloroform, tetrahydrofuran or the like at elevatedtemperatures in the range of about 50C to the boiling point of thereaction mixture. Advantageously, a small amount of a reactioninitiator, such as, azo-bis-butyronitrile or dibenzoyl peroxide, as wellas a hydrogen halide acceptor, for example, pyridine, triethylamine,collidine, allyl chloride, an epoxide or the like can be added. Aresulting 10,1 l-dihydro compound which is mono-halogenated in the l0-or 11- position is subsequently treated with a basic agent, such assodium hydroxide, potassium carbonate, triethylamine, or the like, at atemperature in the range of about room temperature and the boiling pointof the reaction mixture, whereby a 10,1 l-double bond is formed undercleavage of hydrogen halide. Resulting 10,1 l-dihalogen-10,1 l-dihydrocompounds can be reacted i with zinc in ether or dioxan. In this mannera 10,1 l-double bond is also obtained. protecting group bound to thenitrogen atom is then hydrolytically cleaved in the manner describedhereinbefore and there results and amine of the formulas la or lb, whichis unsaturated in 10,1 l-position.

Resulting unsymmetrically substituted compounds of the formulas la or lbwhich carry an exocyclic double bond, as well their salts, can beseparated into their geometric isomers i.e. aand B-isomers. Themethodsof separation are known per se. The geometric isomers are preferablyseparated by fractional crystallisation of the acid addition salts froma solvent, e.g. acetone, or from a solvent mixture, e.g.methanol/diethyl ether.

Resulting unsymmetrically substituted exocyclically saturated compoundsof the formulas la or lb, as well as their salts, are obtained asracemates. They can be separated into their optical isomers according tomethods known per se, e.g. by the reaction with optically active acidssuch as tartaric acids or camphor sulfonic acid and subsequentcrystallisation.

The invention also includes the acid addition salts of the tricyclicamines of formulas la and lb. Such salts are, for example, those formedwith pharmaceutically acceptable organic acids, such as oxalic acid,citric acid, acetic acid, lactic acid, maleic acid, tartaric acid or thelike or withpharmaceutically acceptable inorganic acids, such as,hydrochloric acid, hydrobromic acid, sulfuric acid or the like.

The compounds of formulas la and lb and their pharmaceuticallyacceptable acid addition salts possess psychopharmacologicalantidepressant activity and are therefore useful aspsychopharmacological antidepressants. Moreover, the compounds offormulas la and lb and their salts possess the advantage of being devoidof certain undesirable effects, for instance, they are substantiallyfree of anticholinergic activity and have a very low toxicity.Additionally, the compounds of formulas Ia and lb and their salts havedemonstrated narcosis potentiating, adrenolytic, sedative,antihistaminic and local anesthetic activities. Their usefulpsychopharmacological antidepressant activity is demonstrated inwarm-blooded animals utilizing standard procedures. For example, groupscomprising 10 mice each are administered the test substance in variableamounts subcutaneously. After 16 hours, they are given subcutaneously 5mg/kg of 2-hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-l,2,3,4,6,7-hexahydrol lbl-l-benzyl [a]quninolizine(substance A), and 30 minutes thereafter, they are givenintraperitoneally 3.75 mg/kgof etha nol. A control group of 10 animalsis given only ethanol. The duration of sleep is measured in all animals.The percentage decrease in duration in sleep in comparison with theduration of the substance A potentiated sleep reflects thepsychopharmcological.an-tidepressant effect.

When l-chloro-l0,l l-dihydr0-5-( 3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene, which has an LD of 700mg/kg p.o., is utilized as the test substance at dosages in the range of5-20 mg/kg s.c., a corresponding 32-57% decrease in duration of i sleepis produced.

When l-chloro-5-( 3-dimethylaminopropylidene )-5 H-dibenzo[a,d]cycloheptene, which has an LD of 350 mg/kg p.o., is utilizedas the test substance at dosages in the range of 25-10 mg/kg s.c., acorresponding 48-81% decrease in duration of sleep is produced.

The substantial absence of the anticholingeric effect is demonstrated inrabbits. Pilocarpine "is administered to urethane-narcotized rabbits andtheir saliva drippings are collected in a measuring cylinder over aperiod of 15 minutes. Immediately thereafter, they are given 1,3 or 6mg/kg i.v. of the substance to be evaluated, and their saliva drippingsare collected in a measuring cylinder over a period of 15 minutes. Thesaliva drippings of controls ar also collected over two successiveperiods of 15 minutes each. Teh anticholinergic effect is reported asthe percent inhibition of salivation taken in relation to the salivaproduction before the administration of the test substance. When thel-chloro- 10,1 l-dihydro--(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene is administered in therange of 1-6 mg/kg. i.v., a corresponding 5-19% inhibition of salivaitonis produced. This is much lower than the inhibition obtained withstandard psychopharmacological antidepressants such as amitriptyline.

The compounds of formulas Ia and lb and their pharmaceuticallyacceptable acid addition salts have effects qualitatively similar tothose of amitriptyline, known for its therapeutic uses and properties.Thus, the compounds of this invention demonstrate a pattern of activityassociated with psychopharmacological antidepressants of known efficacyand safety.

The compounds of formulas la and lb can be used as medicaments, forexample, in the form of pharmaceutical preparations which contain themor their salts in admixture with a pharmaceutical, organic or inorganicinert carrier material suited for enteral or parenteral application,such as, for example, water, gelatin. lactose,.starch. magnesiumstearate, talc. vegetable oils, gums, polyalkyleneglycols, and i thelike. The pharamaceutical preparations cna be in solid form, for

,example, tablets, dragees, suppositories, capsules, or in liquid form,for example, as solutions parenteral solutions, suspensions oremulsions. They may be sterilized and may contain additives. such aspreserving. stabilizing, wetting or emulsifying agents, salts forvarying the osmotic pressure or buffers. They may also contain othertherapeutically valuable substances.

A suitable pharmaceutical dosage unit contains from about 1 to 50 mg. ofa compound of formula Ia or lb. Suitable oral dosage regimens inwarm-blooded mammals falls within the range of from about 0.1 mg/kg perday to about 50 mg/kg per day. Suitable parenteral dosage regimens inwarm-blooded mammals falls within the range of from about 0.01 mg/kg perday to about mg/kg per day. However, for any particular subject, thespecific dosage regimen should be adjusted according to individual needand the professional judgement of the person administering orsupervising the administration of a compound of formula la or lb.

The following non-limiting examples further illustrate the invention.All parts are by weight and all temperatures are in degrees centigrade,unless otherwise mentioned.

EXAMPLE 1 Preparation of 1-chloro-l0,l l-dihydro-5-( 3-dimethylaminopropyl)-5H-dibenzo[a.dlcycloheptene 500 g. of 1-chloro-lO,1l-dihydro-5-(3- dimethylaminopropyl )-5-hydroxy-5H-dibenzo[a,dlcycloheptene, 437 g. of red phosphorus, 4.000 ml. of glacialacetic and 2,160 ml. of 57% hydroiodic acid are heated under refluxconditions in an atmosphere of argon for 3 hours. The resultingsuspension is filtered. The filtrate is washed wth 2,000 ml. of

boiling water and subsequently cooled to 20. The crystals which form areseparated by decantation and the mother liquor is concentrated underreduced pressure. The combined residues are suspended in 15,000 ml. ofwater. THe suspension is cooled with ice and, with stirring, adjusted topH 1012 with concentrated caustic soda. The solution is extractedwith4,000 ml. of methylene chloride. The resulting organic phase issuccessively washed with saturated sodium chloride solution and sodiumthiosulfate solution, dried with sodium sulfate evaporated under reducedpressure. The residue is dissolved in 2,000 ml. of ether. The etheralsolution is filtered, and the filtrate is evaporated to yield yellow,oily l-chloro- 10,1 l-dihydro-5-(3-dimethylaminopropyl)-5l-l-dibenzo[a,d]cycloheptene. The hydrochloride ofthis compound crystallizers from acetone/ether and has a melting pointof 149-l53.

The 1-chloro-l0,1 l-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5l-ldibenzo[a,d]cycloheptene employed asstarting material can be prepared as follows:

86.6 g. of Gilman alloy or magnesium turnings are heated under refluxconditions in 800 ml. of absolute ether with a trace of iodine.Subsequently, a solution of 390 g. of dimethylaminopropyl chloride in500 ml. of absolute tetrahydrofuran is added dropwise over a period of 2hours. The resulting mixture is heated under reflux conditions for anadditonal 3 hours. To the suspension obtained previously cooled to 15C.,there is added dropwise over a period of 15 minutes a solution of 242.7g of 1-chloro-10,l l-dihydro 5H dibenzo[a,d lcyclohepten-S-ohe in 500ml. of absolute tetrahydrofuran, and the resulting mixture is heatedunder reflux conditions for 12 hours. Thereafter, the reaction mixtureis cooled to 15, hydrolyzed with 500 ml. of saturated ammonium chloridesolution, filtered, and rinsed with methylene chloride. The filtrate isdried with sodium sulfate and evaporated under reduced pressure. Theresidual yellow substance is recrystallized from 6000 ml. ofhigh-boiling petroleum ether to yield l-chloro-10,1 l-dihydro-S-(3-dimethylaminopropyl)- 5-hdyroxy-5H-dibenzo[a,d]cycloheptene, havinga melting point of l3l-132.

EXAMPLE 2 2082 10. This compound represents a mixture of the twogeometric isomers a+B in the proportion of l :1. The isomeric mixture isrecrystallized from methanol/ether to yield the B-isomer which has amelting point of 222225. The a-isomer crystallizes out from the motherliquour and'has a melting point of 202206.

EXAMPLE 3 Preparation 1-chloro-5-( 3- 19dimethylaminopropylidene)-H-dibenzo[a,d]cy-' cloheptene hydrochoride g.ofl-chloro-5-(3-dimethylaminopropyl)-5-hydroxy-Sl-l-dibenzolad]cycloheptene are heated under reflux conditionsfor-l hour in 50 ml. of absolute ethanol and l 1 ml. of 30% ethanolic'hydrochloric acid. The mixture is evaporated under reduced pressure,taken up in water, washed with either and made alkaline with 2N sodiumhydroxide solution. This solution is shaken out with methylene chloride.The resulting organic phase is washed with water; dried with sodiumsulfate and evaporated to yield l-chloro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene hydrochloride as aviscous oil, having a me tling point of 193-194. This compoundrepresents a mixture of the a and B isomers in the proportion of about1:1. 1

The enrichment of the ,B-isomer can be effected by recrystallizatin ofthe said hydrochloride from methanol/ether. A product containing 75%B-isomer has a melting point of 2l22 19, while a 94% product has amelting point of2l6-221. The B-isomer is produced from the mother liquoras a 97.8% product having a melting point of 991 10.

The l-chloro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene employed as starting material can beprepared as follows:

17 g. of magnesium and 85 g. dimethylaminopropyl chloride are reactedutilizing the procedure of Example 1. The resulting Grignard compound isthen treated with a solution of 52 g. ofl-chloro=5l-l-dibenzo[a,d]cyclohepten-S-one in 500 ml. of absolutetetrahdrofuran. Utilizing the work-up procedure of Example 1, there isobtained l-chloro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene, having a melting point of l34l36.The hydrochloride prepared therefrom has a melting point of 226-227,after recrystallization from methanol/ether.

EXAMPLE 4 Preparation of l-chlorol 0,1 l-dihydro-5-( 3-methylaminopropylidiene)-5H-dibenzocyc1o[a,d]heptene hydrochloride Amixture of g. of l-chloro-lO,l l-dihydro-5-(3-chloropropylidene)-5H-dibenzo[a,d]cycloheptene, 80 ml. of absolutemethanol and 30 g. of methylamine is heated in an autoclave for 12 hoursat 120 under a nitrogen pressure of 6 atmospheres. Subsequently, thesolution is evaporated under reduced pressure and the resulting yellow,oily residue is treated with methanolic hydrochloric acid, wherebyl-chloro-10,l l-dihydro-5-(3-methylaminopropylidene)-5H-dibenzocyclo[a,d- ]heptene hydrochorideseparates out. After recrystallization from methanol/ether, thiscompound has a melting point of 2092 10, and comprises a mixture of the01- and B-i'somers in the proportion of about 3:2.

The "l-chloro-l0,1l-dihydro-5-(3-chloropropylidene)-5H-dibenzofa,d]cycloheptene used as starting materialcan be prepared as follows:

To 14 g. of Gilman alloy in 100 ml. of absolute ether, after theaddition of a trace of iodine or methyl iodide,

there is added dropwise a solution of 45.6 g. of

l-chloro-3-meth0xypropane in 300 ml. of absolute ether over a period of30 minutes under reflux'condi tions. The reaction mixture is heated foran additional 3 hours. After cooling to 20, a solution of 48.5 g. oflchlorol 0,1 l-dihydro-S H-dibenzo[a,d]cyclohepten- 20 S-one in 160 ml.of tetrahydrofuranis added over a period of 30 minutes. This reactionmixture, after being heated under reflux conditions for 12-hours, ishydrolyzed with 150 ml. of saturated ammonium chloride solution withcooling, filtered, rinsed with chloroform, dried with sodium sulfate andevaporated. The 1- chlorol 0,1 l-dihydro-5-( 3-methoxypropyl)-5-.hydroxy-5'H-dibenzo[a,d]cycloheptene obtained hasa melting point of 8l,after recrystallization from ether/petroleum ether. 53.3 g. of1-chloro-l0,1 ldihydro- 5-( 3-methoxypropyl)-5-hydroxy-5 H-dibenzo[a,d]cyloheptene are heated under reflux conditions for 1 hour in250 ml. of methanol and 53 ml. of 30% methanolic hydrochloric acid.Thereafter, the mixture is evaporated under reduced pressure, taken upin ether, washed with water, dried with sodium sulfate and reevaporatedto yield l-chloro-lO,1 l-dihydro- 5-(3-methoxypropylidene)-5H-dibenzo[a,d]cycloheptene as a yellow oil.

48.5 g. of 1-chloro-10,l1-dihydro-5-(3-methoxypropylidene)-5H-dibenzo[a,d]cycloheptene are dissolved in 150ml.of methylene chloride. The resulting solution is cooled to 10 andtreated over a period of 15 minutes with a solution of 30 g. of borontrichloride in 150 ml. of methylene chloride. The reaction mixture isstirred at roomtemperature for 19 hours, and thereafter it is poured onice-water, extracted with methylene chloride, washed with water anddried over sodium sulfate. After evaporation, there is obtained 1-chloro- 10,1 1-dihydro-5-( 3-chloropropylidene)-5H-dibenzo[a,d]cycloheptene as a yellow-orange oil which slowlycrystallizes out and has a melting point of EXAMPLE 5 Preparation of1-chloro-5-( 3- methylaminopropylidene)-5H-dibenzo[a,d]cycloheptenehydrochloride If the l-chloro-lO,l l-dihydro-5-(3-chloropropylidene)-5l-I-dibenzo[a,d]cycloheptene of Example 4 isreplaced by a l-chloro-5-(3-chloropropylidene)-5l-l-dibenzo[a,d]cycloheptene, under otherwisesimilar conditions, there is obtianed l-chloro-5-(3-methylaminopropylidene-S H-dibenzo[a,d]cycloheptene hydrochlroide. Amixture of the two aand'B-isomers of this compound has a melting pointof 2082 1 6.

\ The 1-chloro-5-( 3-chloropropylidene )-5H-dibenzo[a,d]cyclohepteneemployed as starting material for this reaction can be prepared asfollows;

To 10.5 g. of- Gilman alloy in ml. of absolut ether, after the additionof a trace of iodine and 1-3 drops of methyl iodide, there is addeddropwise a solution of 34.1 g. of 1-chloro-3-methoxypropane in 300 ml.of absolute ether overa period of 30 minutes under reflux conditions.After the addition of ml. of tetrahdyrofuran, the reaction mixture isheated for an additional 3 hours. Thereafter, it is cooled to 20 and asolution of 36 g. of 1-chloro-5l-l-dibenzo[a,d]cyclohepten-S-one in 300ml. of tetrahydrofuran is added over a period of15 minutes. Thisreactionmixture,-after being heated under reflux conditions for 15 hours, is'hydrolyzed with 150 ml. of saturated ammonium chloride solution withcooling, filtered, dried with sodium sulfate and evaporated underreduced pressure to yield l chloro-5 3-methoxypropyl )-5-hydroxy-5 H-dibenzo[a,d]cycloheptene as a yellow, viscous oil.

50 g. of 1-chloro-5( 3-methosypropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptane are dissolved in 250 ml. of absolute methanol.heated under reflux conditions for 1 hour with 50 ml. of 30% methanolichydrochloric acid, and subsequently concentrated under reduced pressure.The residue is taken up in ether, washed with water, dried with sodiumsulfate and evaporated to yield1-chloro-5-(3-methoxypropylidene)-5H-dibenzo[a,d]cycloheptene as a redoil.

42.8 g. of l-chloro-5-(3-methoxypropylidene)-5H-dibenzo[a,d]cycloheptene are cooled to l in 150 ml. of methylenechloride. A solution of 26.7 g. of boron trichloride in 150 ml. ofmethylene chloride is then added dropwise over a period of 15 minutes.The reaction mixture is stirred at room temperature for 19 hours.Subsequently, the mixture is poured on icewater. extracted withmethylene chloride, washed with water and dried with sodium sulfate. Theresidue is taken up in benzene and purified by filtration with 300 g. ofsilica gel to yield 1-chloro-5-(3-chloropropylidene)-H-dibenzo[a,d]cyc1oheptene as a red oil which, aftercrystallization from petroleum ether, has a melting point of 5360.

"EXAMPLE 6 Preparation of l-chloro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cyc1oheptene 5.6 g. of magnesium turnings are suspendedin 100 ml. of absolute tetrahydrofuran and treated with a trace ofiodine and methyliodide. To this mixture there is added dropwise asolution of 26 g. of dimethylaminopropyl chloride in 100 ml. oftetrahydrofuran over a period of about 20 minutes under refluxconditions. The mixture is boiled for an additional 3 hours. Aftercooling the mixture to 20, 21 solution of 25.2 g. of 1,5-dichloro-5l-l-dibenzo[a,d]cycloheptene in 250 ml. of tetrahydrofuran isadded dropwise over a period of minutes. The mixture is subsequentlyheated under reflux conditions for 15 hours, cooled and hydrolyzed with200 ml. of saturated ammonium chloride solution. The resulting mixtureis filtered and rinsed with methylene chloride. The filtrate is driedwith sodium sulfate and evaporated under reduced pressure to yield 1-chloro-5-(3dimethylaminopropyl)-5H-dibenzo[a,d- ]cycloheptene as aviscous oil which has a boiling point of about 160/0.0l mm.

EXAMPLE 7 Preparation of l-chlorol 0,1 1-dihydro-5-( 3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene hydrochloride A solutionof 102.5 g. of l-chloro-10,l 1-dihydro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene in 500 ml. ofmethylene chloride is added dropwise to a solution of 55 g. of cyanogenbromide in 500 ml. of methylene chloride. The reaction mixture isstirred at room temperature for 12 hours and subsequently poured onice-water. The methylene chloride phase is washed with 2N hydrochloricacid and water, dried with sodium sulfate and evaporated under reducedpressure. The residue obtained is a yellow oil which is crystallizedfrom ether to yield l-chloro- 10,1 l-dihydro-5-( 3-N-cyano-Nmethylarninopropyl)- 5H-dibenzo[ a,d]cycloheptene, having a meltingpoint of 697 1. After being dissolved in benzene/ether, this compoundcan be chromatographically purified on 500 g. of silica gel.

A mixture of 650 g. of 1-ch1oro-l0,1 1-dihydro-5-(3-N-cyano-Nmethylaminopropyl)-5H-dibenzo[a,d]cycloheptene, 4,000 ml. ofglacial acetic, 2,000 ml. of water and 1,000 ml. of concentratedhydrochloric acid are heated under reflux conditions for 24 hours. Thereaction mixture is concentrated under reduced pressure, diluted with20,000 m1. of ice-cold water and washed with 5,000 ml. of methylenechloride. The mixture is made alkaline with a concentrated sodiumhydroxide solution and the resulting precipitation is taken up inmethylene chloride. Following concentration of the methylene chloridesolution, there is obtained a brown-red oil which is converted into thecrystalline 1-chloro-10,1 l-dihydro-5-( 3-methylaminopropyl)5H-dibenzocyclo[a,d]heptene hydrochloride by addition of methanolichydrochloric acid. After recrystallization from methanol/ether, thiscrystalline compound has a melting point of 168-l69.

EXAMPLE 8 Preparation of l-chloro-5-(3,-methylaminopropylidene)-5l-l-dibenzo [a,d]cycloheptene A solution of5.4 g. of l-chloro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene hydrochloride isadded dropwise to a solution of 2.1 g. of cyanogen bromide in 20 ml. ofmethylene chloride. The reaction mixture is stirred at room temperaturefor 20 hours and subsequently washed with water. 2N hydrochloric acidand water, dried with sodium sulfate and evaporated to yield1-chloro-5-(3-Ncyano-N-methylaminopropylidene)-5H-dibenzo[a,d]cyc1oheptene as a yellowoil which is dissolved in benzene and chromatographically purified on 50g. of silica gel.

A mixture of 4.4 g. of l-chloro-5-(3-N-cyano-N-methylaminopropylidene)-5H-dibenzo[a,d]cycloheptene, 40 ml. of glacialacetic, 24 ml. of water and 8 ml. of concentrated hydrochloric acid areheated under reflux conditions for 24 hours. The reaction mixture isworked up according to the procedure of Example 3 to yieldl-chloro-5-(3-methylaminopropylidene)-5l-ldibenzo[a,d]cycloheptene as ared oil. The corresponding hydrochloride salt has a melting point of208-216 and comprises a mixture of the aand B-isomers. Throughrecrystallization from methanol/ether, there is obtained the a-isomer,which has a melting point of 2l8-224.

EXAMPLE 9 Preparation of l-fluorol 0,1 1-dihydro-5-(3-dimethylaminopropylidene)-5l'l-dibenzo[a,d]cycloheptene 15 g. of1-fluoro-10,1l-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5-H-dibenzo[a,d]cycloheptene are heatedunder reflux conditions for-2 hours with ml. of absolute ethanol and 12ml. of 30% ethanolic hydrochloric acid. The resulting reaction mixtureis evaporated under reduced pressure, and is worked up in the manner setforth in Example 1 to yield l-fluorol 0,1 l-dihydro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d] cycloheptene, thehydrochloride of which has a melting point of 187-200 afterrecrystallization from methanol/ether. The compound comprises a mixtureof the aand B-isomers.

} The 4 l-fluoro-l0,l l-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycIoh'eptene employed asstarting material can be prepared as follows:

14.8 g of pulverised phthalic anhydride, 18.5 g of or thofluorophenylacetic acid and 0.5 g of freshly melted sodium acetate are heated for 3hours at 235-240C and th'e'resulting water is distilled off. The hotreaction mixture is transfered into a mortar and pulverised. Thecrudeproduct is recrystallised from acetone/petroleum ether. There isobtained ortho-fluorobenzylidene phthalide, which melts at l48l5 lC.

72.6 g of ortho-fluorobenzylidene phthalide are heated in an argonatmosphere for 24 hours under reflux conditions together with 55.0 g ofred phosphorus and 450 ml of hydroiodic acid (density 1.75 The reactionmixture is cooled, supplied with 500 ml of-water and filtered. Theresidue is heated with 2N caustic soda to 80C and again filtered toremove the phosphorus.

The alkaline solution is acidified and extracted with methylenechloride, washed with water, dried and evaporated to dryness. The crudeproduct obtained is recrystallised from acetone/low boiling petroleumether. 2-(ortho-Fluorophenethyl)-benzoic acid is obtained as whitecrystals melting at 93-94C.

280 g of poly-phosphoric acid are heated to 120C and, in an atmosphereof argon, 70.0 g of 2-(orthooxide fluorophenethyl)-benzic acid areadded. The heating 1 is continued over a 3 hour period at 150C, thereaction mixture is poured over ice water and extracted with ether. Theether extract is washed with water, 2N caustic soda and again with wateruntil neutral, dried over sodium sulphate, filtered and evaporated todryness.

The residual crude product is distilled under reduced pressure. There isobtained 1-fluoro-10,11-dihydro- 5H-dibenzo[a,d]cycloheptene-5-one as ayellow oil which crystallises upon standing, m.p. 64-65C. 19.1 g. ofGilman alloy and a trace of iodine are suspended in 150 ml. of absoluteether, and are reacted with 88 g. of dimethylaminopropyl chloride in 200ml. of tetrahydrofuran as in Example 1. To the resulting suspensionthere is added dropwise at 20 a solution of EXAMPLE Preparation of1-fluoro-l0.1 l-dihydro-5-( 3- dimethylaminopropyl )-5 H-dibenzo[ a.d]cycloheptene g. of l-fluoro-10.1 l-dih'ydro-5-(3- dimethylaminopropyl)-5-hydroxy-5H-dibenzo[ a,d]cycloheptene are heated under refluxconditions for 3 hours in an atmosphere of argon with 14 g. ofred'phosphorus. 250 g. of glacial acetic and 70 ml. of 57% hydroiodicacid. Thereafter, the mixture is filtered hot and the filtrate isconcentrated under reduced pressure. The residue is treated with 2Nsodium hydroxide solution and is taken up in methylene chloride. Thegreenish oil which forins is then purified by chromatography in benzenesolution on the -fold amount of aluminum to yieldl-fluoro-10,l1-dihydro-5-(3-dimethylaminopropyl)-5l-l-dibenzo[a,d]cycloheptene, the hydrochloride ofwhich has a melting point of 169170, after recrystallization frommethanol/ ether.

EXAMPLE 11 pressure, whereby there is obtained a mixture consisting ofthe a and B-isomers of l-chloro-lO (or 11)-bromo-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptenehydrochloride. This mixture is dissolved in water, made alkaline by theaddition of 2N sodium hydroxide solution and extracted with chloroform.The chloroform extract is dried with sodium sulfate, filtered andevaporated. The resultingresidue is dissolved .in benzene and filteredon the 30-fold amount of aluminum oxide (activity grade ll). Thefiltrate is evaporated, acidified with methanolic hydrochloric acid andreevaporated. The residue is treated with acetone, whereby l-chloro-lO(or 11)-bromo-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene hydrochloridewhich has a melting point of 221224 and consists of 96.5% a-isomer and3.5% ,B-isomer whichcrystallizes out. The B-isomer can be obtained fromthe mother liquor.

The l-chloro-lO (or 11)-bromo-5-(3- dimethylaminopropyl)-5-hydroxy-5l-l-dibenzo[a,d]cycloheptene employed as starting material canbe prepared as follows:

21.3 g. of 1-chloro-5l-l-dibenzo[a,d]cyclohepten -5-one are suspended in200 ml. of carbon tetrachloride. The resulting mixture is treated over aperiod of about 45 minutes with a solution of 14 g. of bromine in 40 ml.of carbon tetrachloride. At the same time, the reaction mixture isirradiated with a 500 W lamp. After complete addition, the reactionmixture is irradiated for an additional 30 minutes. Subsequently, it isstirred for 12 hours and then filtered. The recovered fine precipitateis washed with petroleum ether and dried under reduced pressure. Thel-chloro-l0 ,l l-dibromo- 10,1 1-dihydro-5l-l-dibenzo[a,d]cyclohepten-5-one obtained (which melts at l69-l70 withdecomposition) is immediately suspended in 300 m1 of ethanol, treatedwith a solution of 5.5 g of potassium hydroxide in 10 ml of water andheated under reflux conditions for 4 hours. The reaction mixture isevaporated to dryness under reduced pressure, taken up in ether, washedwith water and dried with sodium sulfate. The dried ethereal solution isconcentrated to 500 ml. to yield crystalline l-chloro- 10 (or 1 1)-bromo-5l-l-dibenzo[a,d]cyclohepten-S-one, having a melting point of127, after recrystallization from ethanol.

2.76 g. of Gilman alloy are heated in 10 ml. of absolute ether with atrace of iodine and a few drops of methyl iodide. A soltition of 10.5 g.of dimethylaminopropyl chloride in 50 ml. of absolute tetrahydrofuran isadded dropwise over a period of 1 hour. The resulting mixture is heatedunder reflux conditions for 1 hour.

To the suspension obtained previously cooled to 05, there is addeddropwise over a period of 40 minutes a solution of 17.3 g. ofl-chloro-lO (or l1)-bromo-5H- dibenzo[a,d]cyclohepten-S-one in 100 ml,of absolute tetrahydrofuran. This mixture is heated under refluxconditions for 3 hours. Thereafter, the reaction mixture is hydrolyzedwith 20 ml. of saturated ammonium chloride solution with cooling and isfiltered. The residue is rinsed with ether. The combined filtrates aredried with sodium sulfate and evaporated to yield l-chloro-lO (or 1 1)-bromo-5-(3-dimethylaminopropyl)-5-hydroxy-5l-ldibenzo[a,d]cycloheptene, having amelting point of 1 17l 18, after recrystallization from 150 ml. ofhighboiling petroleum ether.

EXAMPLE 12 Preparation of the aand ,B-isomers of 1.10 (or 11)-dichloro-5-( 3-dimethylaminopropylidene )-5H-dibenzo[a,d]cycloheptenehydrochloride 25 g. of 1,10 (or ll)-dichloro-5-(3-dimethylaminopropyl)-5-hydroxy-5H dibenzo[a,d]cycloheptene are heatedunder reflux conditions for 15 hours with 100 ml. of absolute ethanoland 150 ml. of 30% ethanolic hydrochloric acid. The reaction mixture isconcentrated under reduced pressure. The residue is dissolved in water,made alkaline with 2N sodium hydroxide solution and extracted withmethylene chloride. The methylene chloride extract is washed with water,dried with sodium sulfate and evaporated to yield 1,10 (or 1 l)-dichloro-5-(3- dimethylaminopropylidene)-5H-dibenzo[a,d]cyclohepteneas a yellow oil. For purification, this oil is taken up in benzene andfiltered on 200 g. of aluminum oxide. The product obtained represents amixture of the aand B-isomers in the proportion of about 1:1. By

conversion of this product. into the corresponding hydrochloride andrecrystallization from acetone, there first separates out a producthaving a melting point of 222-224, which comprises 94% of the a-isomerand 6% of the B-isomer of 1,10 (or ll)-dichloro-5-(3-dimethylaminopropylidene)-5l-ldibenzo[a,d]cycloheptene hydrochloride.From the mother liquor there is obtained a product having a meltingpoint of 132-l40 and which consists of 17% a-isomer and 83% B-isomer. Afurther enrichment of the B-isomer is possible by repeatedcrystallizations.

The 1,10 (or 1 l )-dichloro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene employed asstarting material can be prepared as follows:

51.6 g. of 1-chloro-5l-l-dibenzo[a,d]cyclohepten- 5-one are dissolved in300 ml. of carbon tetrachloride. With heating at about 60 andirradiation with a 500 W lamp, an 18% (weight for volume) solution ofchlorine in carbon tetrachloride is added dropwise over a period of .10minutes. The reaction mixture is irradiated for an additional 10 minutesand subsequently cooled. The l,10,1 l-trichlorol 0.1 1-dihydro-5 H-dibenzo[a,d]cyclohepten-S-one which crystallizes out is removed byfiltration, dried, immediately dissolvedjn 760 ml. of ethanol andtreated with 33 g. of potassium carbonate and 30 ml. of water. Thismixture is heated under reflux conditions for 8 hours. The crystalswhich separate out on cooling are removed by filtration and taken up inchloroform. The chloroform solution is washed with water, dried,filtered and evaporated. After recrystallization from ethanol, theresidue yields 1.10 (or 1 l )-dichloro-5H-dibenzo[a,d]cyclohepten- 5-oneas long needles having a melting point of l43-145.

6.04 g. of Gilman alloy are heated in 20 ml. of absolute ether with atrace of iodine and a drop of methyl iodide and a solution of 21.9 g. ofdimethylaminopropyl chloride in 100 ml. of absolute tetrahydrofuran issubsequently slowly added dropwise. The reaction mixture is heated at 50for 2 hours. After cooling to 0, a solution of 33 g. of 1,10 (or11)-dichloro5H-dibenzo[a,d-

]cyclohepten-S-one in 200 ml. of absolute tetrahydro are dried withsodium sulfate, filtered and evaporated a under reduced pressure.v Afterrecrystallizationfrom high-boiling petroleum ether, the residue yields1,10 (or 1 1 )-dichloro-5-( 3-dimethylaminopropyl)-5-hydroxy-5l-l-dibenzo[a,d]cycloheptene, having a melting point of 9294.

EXAMPLE 13 Preparation of the 01- and ,B-isomers of 1,3-dichloro- 10,1l-dihydro-5-(3-dimethylaminopropylidene)-5H- dibenzo[a,d]cycloheptenehydrochloride i 25 g. t of 1,3-dichloro-l0,1l-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene are heatedwith 250 ml. of 30% ethanolic hydrochloric acid under reflux conditionsover a 15- hour period. After evaporation under reduced pressure, thereaction mixture is dissolved in water, washed with ether and madealkaline with dilute sodium hydroxide solution. After extraction byshaking with ether and evaporation to dryness, the remainingoilymixtures of the isomers of. ,1 .3-dichloro-l0,l l-dihydro-5-(3-.dimethylaminopropylidene )-5 H-dibenzo[a,d ]cycloheptene by treatmentwith a methanolic hydrochloric acid is converted to the hydrochloride.Following the recrystallization from acetone, the hydrochloride of thea-isomer precipitates, which has a melting point of 23 l233. From themother liquors one obtains through crystallization from methanol/ether aproduct which is 94% of the hydrochloride of the B-isomer, having amelting point of l80l83.

The starting material 1,3-dichloro-10,l bdihydro-S-(3-dimethylaminopropyl )-5-hydroxy-5H-dibenzo[a,d- ]cycloheptene can beprepared as follows:

50 g. of 2-(2,4-dichlorophenethyl)-benzoate and 100 ml. ofthionylchl'oride are heated together under reflux conditions over a4-hour period. Following concentration under reduced pressure, theresulting acid chloride is dissolved in 500 ml. of carbon disulfide andis added dropwise to a boiling suspension of g. of aluminum chloride in1.1 carbon disulfide. After boiling for 4 hours, the reaction mixture isevaporated under reduced pressure, hydrolyzed with ice and extractedwith ether, with water and 2N sodium hydroxide solution, and washed withwater, dried and evaporated. The

crude 1,3-dichloro-10,l l-dihydro-5H-dibenzo[a,d]cy- "271,3-dich1oro-10,l 1-dihydro-5 3- dimethylaminopropyl)--hydroxy-5H-dibenzo[ a,d]cycloheptene, which is then immediatelyreacted further.

EXAMPLE l4 Preparation of 1,3-dichlorol 0,1 1 dihydro-5-(3-dimethylaminopropyl)-5H'-dib'enzo[a,d]cyclohep'tene hydrochloride 23.5g. of l,3-dichloro-10,1 l-dihydro-5-(3-dimethylaminopropyl)-5Hhy'droxy-5H-dibenzo[a,d- ]cycloheptene are mixedwith 19 g. of red phosphorus, 320 ml. of glacial acetic acid and 100 ml.of hydroiodic acid (having a specific gravity of 1.75), and the reac-'tion mixture is heated for 4 hours at 1 in an atmosphere of argon.Whereupon, the reaction mixture is filtered hot. While cooling, thehydroiodide-of 1,3- dich1oro-l0,1 l-dihydro-5=( 3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene separates out and is taken up in water.Through the addition of 2N sodium hydroxide solution, the base separatesout and is taken up in methylene chloride. And, after washing with wa-'ter, is dried with sodium sulfate, filtered and evaporated. The residueis a yellow oil, which through the ad dition of ethanolic hydrochloricacid and ether separates out as the crystalline hydrochloride of 1,3-dichloro-10.1 1-dihydro-5-( 3-dimethylaminopropy1)-5H-dibenzo[a,d]cycloheptene. The product is hydroscopic and melts at168169.

EXAMPLE 1 5 1,9-dichloro-l0,1 1'-dihydro-5-(3- Preparation ofdimethylaminopropylidene)-5l-l-dibenzo[a,d]cy-' cloheptene 4.1 g. ofl,9-dichloro-10,l l-dihydro 5-( 3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene are heated in100 ml. of 30% ethanolic hydrochloric acid under reflux conditions for 2hours. After evaporation under reduced pressure, the residue isdissolved in water, washed with ether and made alkaline with sodiumhydroxide solution and taken up in ether. Following evaporation of theethereal residue, the oily l,9-dichloro-10,ll-dihydrodimethylaminopropylidene)-5l-l-dibenzo[a,d]cycloheptene isdissolved in benzene, purified by filtration with 50 g. of aluminumoxide and converted to the hydrochloride which after recrystallizationfrom methanol/ether has a melting point of 234-235.

The starting material 1,9-dichl0ro-l0,1 l-dihydro-5-(3-dimethylaminopropy1)-5-hydroxy-5l-l-dibenzo[ a,d- ]cycloheptene canbe prepared as follows:

18.2 g. of 3-chloro-phthalic anhydride and 20.5 g. of (2-chlorophenyl)acetic acid are melted with 0.5 g. of sodium acetate. The molten mass ispoured into 120 ml. of ethanol withh stirring, cooled and filtered. Theresulting mixture of the isomers 4-chloro-3-(2- chlorobenzylidene)phthalide (A) and 7-chloro-3-(2- chlorobenzylidene)-phthalide (B) has amelting point of 159-190. The separation of the isomers 'is'accomplishedthrough recrystallization from acetone. The desired isomer (A)precipitates in over 96% purity and.

has-a'melt'ing point of 204209. 53 g. of the resulting isomer (A)'in 300ml. of hydroiodic acid of specific gravity 1.75 are heated together with40 g. of red phos- I 2N sodium hydroxide solution, and the solution isagain filtered to remove the residual phosphorus. The filtrate isacidified with concentrated hydrochloric acid and is extracted withmethylene chloride. The methylene chloride extract is washed with water,dried with sodium sulfate and evaporated. The resulting 4-ch1oro-3-.(2echlorobenzyl)-phtha1ide, after recrystallization from acetone/lowboiling petroleum ether, has a melting point of 129 -l30. 32.5 g. Y of4-chloro-(2- chlorobenzyl)-phthalide are dissolved in a solution of 14g. of potassium hydroxide in 350 ml. of water. Following concentrationof the reaction mixture under reduced pressure,potassium-[3-chloro-2-(2-ch1oro-ahydroxy-phenethyl)-benzoate]is obtainedas a solid foam. 48.6 g. of potassium[3-chloro-2-(2-ch1oro-ahydroxy-phenethyl)ebenzoate]are dissolved in and300 ml. of dimethylsulfoxide and heated at 170 for 3 /2 hours in anatmosphere of argon. The reaction product is poured over ice-water andthe entire mixture is acidified with 2N hydrochloric acid and extractedwith methylene chloride. The methylene chloride extract is washed withwater, dried with sodium sulfate and concentrated to yield3-chloro-2-(2-chlorostyryl)- benzoate, having a melting point ofl51-155.

15 g of 3-ch-loro-(2-chlorostyryl)-benzoate are dissolved in 250 m1. ofhydroiodic acid having a specific gravity of 1.75 and are agitated with12 g. of red phosphorus over a 24-hour period at The reaction mixture isthereafter mixed with 200 ml. of water and filtered. The residue isdissolved in 50% sodium hydroxide solution with warming. Followingfiltration of the phosphorus residue, the solution is washed with ether,acidified with concentrated hydrochloric acid and extracted withmethylene chloride. The methylene chloride extract is dried with sodiumsulfate and evaporated to yield benzoate, having a melting point ofl37139.

50 g. of polyphosphoric acid are heated to 120, and, in an atmospihereof argon, 7 g. of 3-chloro-2-(2- chloro-phenethyl)-benzoate are added.The heating is continued over a 5-hour period at The reaction mixture ispoured over ice and extracted with benzene. The benzene extract iswashed first with 2N sodium hydroxide solution and then with water,dried over sodium sulfate and evaporated to yield 1,9-dich1oro- 10,11-dihydro-5l1-dibenzo[.a,d]cyclohepten-5-one, which afterrecrystallization from acetone/low boiling petroleum ether has a meltingpoint of l85-187.

Through the utilization of 1.1 g. of Gilman alloy, 5.3 g. ofdimethylaminopropyl chloride and 3.4 g. of 1,9- dic hloro-10,11-dihydro-5l-1-dibenzo[ a,d]cyclohepten- 5-one, one obtains, accordingto the procedure of Example l, 1,9-dichloro-l0,1l-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5 H-dibenzo[a,d]cycloheptene as a yellowoil, which is then immediately reacted further- EXAMPLE 16 Tablets areprepared utilizing the following composition:

hcptcne hydrochloride 28.05 g. Lactose r 1 10 g. Maize starchi t 1 57.95g. Talcum 3.40 g. Magnesium stearate 0.6 g.

3-chloro-2-( 2-chlorophenethyl The ingredients are mixed together andcompressed into tablets of 200 mg. each. Subsequently, they are coatedwith ethyl cellulose and Carbowax.

5 R3 EXAMPLE l7 Tablets are prepared utilizing the followingcomposition: P

. l l-chloro--(3-d1methylum|nopropylldene SH-dibenzola.d]cycloheptenehydrochloride 28405 g. Lactose l 10 g. Maize starch 57.95 g. Talcum 3.40g. Magnesium stearute 0.6 g.

wherein R is chlorine or fluorine, R and R are hydrogen, chlorine orfluorine, X is ethylene, vinylene or a halo-substituted vinylene, one ofP or P is hydrogen and the other is hydrogen or hydroxyl, or P and Ptaken together represent an additional bond, Q is ben- The ingredientsare mixed together and compressed into tablets of 200 mg. each.Subsequently, they are coated with ethyl cellulose and Carbowax.

We claim: l. A compound of the formula enesulfomc acld' zylidene, and Bis the anion of an acid selected from the 20 group consisting ofhydrochloric acid, sulfuric acid,

methane-sulfonic acid, benzenesulfonic acid and tolu- UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,884,967

DATED j May 20, INVENTOR(S) Emilio Kyburz & Hans Spiegelberg It iscertified that error appears in the above-identified patent and thatsaid Letters Patent Q are hereby corrected as shown below:

Cover Sheet, after [60] Related U .S Application Data" insert:

. [30] Foreign Application Priority Data Nov. 8, 1966 Switzerland16144/66 Feb. 2, 1967 Switzerland 1651/67 Btgncd and Scaled thiseighteenth Day of November 1975 [SEAL] Arrest:

RUTM C. MASON C. MARSHALL DANN JIIHSIIHX ()jj'iu'r ('ummiisi'vm'r ii]luu'nlx and Trademarks

1. A COMPOUND OF THE FORMULA